title: Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues.
abstract: Systemic therapy with anti-VEGF drugs such as bevacizumab is widely used for treatment of human patients with various solid tumors. However, systemic impacts of such drugs in host healthy vasculatures remain poorly understood. Here, we show that, in mice, systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody caused global vascular regression. Among all examined tissues, vasculatures in endocrine glands, intestinal villi, and uterus are the most affected in response to VEGF or VEGFR-2 blockades. Thyroid vascular fenestrations were virtually completely blocked by VEGF blockade, leading to marked accumulation of intraendothelial caveolae vesicles. VEGF blockade markedly increased thyroid endothelial cell apoptosis, and withdrawal of anti-VEGF resulted in full recovery of vascular density and architecture after 14 d. Prolonged anti-VEGF treatment resulted in a significant decrease of the circulating level of the predominant thyroid hormone free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid functions. Conversely, VEGFR-1-specific blockade produced virtually no obvious phenotypes. These findings provide structural and functional bases of anti-VEGF-specific drug-induced side effects in relation to vascular changes in healthy tissues. Understanding anti-VEGF drug-induced vascular alterations in healthy tissues is crucial to minimize and even to avoid adverse effects produced by currently used anti-VEGF-specific drugs.
authors.affiliation: Department of Microbiology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Yang
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ziquan
authors.initials: Z
authors.lastname: Cao
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Yang
authors.forename: Hideki
authors.initials: H
authors.lastname: Iwamoto
authors.forename: Eric
authors.initials: E
authors.lastname: Wahlberg
authors.forename: Toste
authors.initials: T
authors.lastname: Länne
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D021941:Caveolae / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D041981:Gastrointestinal Tract / Q000098:blood supply* / Q000187:drug effects; D005836:Genitalia, Female / Q000098:blood supply* / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D013961:Thyroid Gland / Q000098:blood supply / Q000648:ultrastructure; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D057134:Antibodies, Neutralizing; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: angiogenesis; antiangiogenic therapy; off-tumor targets; vascular homeostasis; vessel regression